1. Field of the Invention
This invention relates to a novel implant capable of releasing a therapeutic agent at a constant rate over a prolonged period of time, and a method for treating a mammalian or avian subject using said implant.
2. Related Disclosure
The advantages of employing sustained-release drug implants are well known in the art. Many therapeutic agents are rapidly metabolized or are cleared from the subject's system, necessitating frequent administration of the drug to maintain a therapeutic concentration. There exists a need for a sustained release device capable of administering an active compound at a relatively constant rate, where the rate is high enough to effect and maintain an effective concentration. Preferably, such a device would be inexpensive and easily manufactured.
Steroids are frequently administered to livestock to increase feed efficiency. For example, steroids such as progestogen derivatives are frequently administered to beef cattle to increase the quality of the meat produced, and increase the yield of meat per amount of feed consumed. Progestongens are more effective when coadministered with an estrogen derivative. For example, Synovex.RTM. S implants, which are administered to steers, are cylindrical pellets containing a mixture of estradiol benzoate and progesterone. Estrogen may not be administered orally, necessitating a parenteral form of delivery.
There is a variety of means by which the art has attempted to prepare suitable sustained release devices. Such devices may be designed typically for oral, rectal, or subcutaneous administration. The mode of administration is usually critical to the design of a sustained release device, due to the difference of biological environment. For example, a device for subcutaneous implantation must be non-irritating, and must be mechanically strong enough to withstand flexion or impact. A device for oral administration must be designed for resistance to gastric acidity and sensitivity to pH change.
Some devices are "matrix" type, and consist of an active compound dispersed in a matrix of carrier material. The carrier material may be either porous or non-porous, solid or semi-solid, and permeable or impermeable to the active compound. Matrix devices may be biodegradable, i.e., they may slowly erode after administration. Alternatively, matrix devices may be nondegradable, and rely on diffusion of the active compound through the walls or pores of the matrix. Matrix devices may be easily prepared, but are not suitable for administering some compounds. It is extremely difficult to prepare matrix devices that release active compound at a constant rate (i.e., zero order kinetics), as the release rate is typically a function of the active compound's concentration in the matrix. We are unaware of any published example of zero order release from a matrix device. As the amount of active compound remaining declines, the rate of release diminishes.
Other devices are "reservoir" type, and consist of a central reservoir of active compound surrounded by a rate controlling membrane (rcm). The rcm may be either porous or non-porous, but is not usually biodegradable. It is typically easier to prepare a reservoir device capable of zero order kinetics (independent of active compound concentration), as the release rate often depends only on the surface area of the rcm. However, reservoir devices often suffer from an inadequate rate of delivery: the rcm surface area required to maintain an effective concentration of active compound is frequently so large that it is impractical to administer the device. Additionally, reservoir devices are sensitive to rupture: if the rcm is breached, an excessive (possibly lethal) dose of active compound may be released instantaneously.
Some sustained release devices are hybrids, having a matrix core surrounded by a rcm. Other sustained release devices may be mechanical in nature, and include small compound-filled electrical or osmotic pumps. While these devices may be capable of zero order release, they are typically too expensive to compete economically with matrix and reservoir devices.
A number of implant devices are known in the art. UK Patent Application 2,010,676 to Wong, et al. discloses a reservoir device in the form of a flat, heat-sealed packet, cylindrical tube or "T" vaginal insert, comprising a rate controlling membrane, specifically ethylene-vinyl acetate copolymer or butylene terephthalate/polytetramethylene ether terephthalate. The active compound is presented in a carrier which is water-imbibing (to maintain, but not increase the size of the implant), and viscous to improve drug distribution within the device. These implants are useful for administering progesterone, estradiol, or d-norgestrel.
H. Nash, et al., "Steroid Release From Silastic Capsules and Rods" Contraception, 18, 367-394 (1978) discloses both reservoir and matrix implants fashioned from Silastic.RTM. polydimethylsiloxane, for sustained administration of contraceptive steroids. Nash's reservoir devices comprise Silastic.RTM. tubes (1.57 mm I.D., 2.41 mm O.D., and 2 or 3 cm in length) filled with steroid crystals. The matrix devices were prepared by mixing Silastic.RTM. monomer and steroid (25% by weight) with the catalyst, and pressing into molds to form rods 2.4 mm.times.2 or 3 cm. The steroids used were levonorgestrel, norethindrone, norethindrone acetate, testosterone, testosterone propionate, megestrol acetate, norgestrienone, norethandrolone, 17.beta.-hydroxy-17.alpha.-ethynyl-18-methyl-4,9,11-estriene-3-one, 17.alpha.-ethyl-17-hydroxy-4-norandrosten-3-one, 16-methylene-17.alpha.-acetoxy-19-norpregn-4-en-3,20-dione, and 17.alpha.,21-dimethyl-19-norpregna-4,9-dien-3,20-dione. None of the implants released steroid with zero order kinetics. The average release rate in vivo ranged from 3.5 .mu.g/cm/day (levonorgestrel for 367 days in humans) to 82.7.+-.65 .mu.g/cm/day (norethandrolone for 14 days in rats: the average rate after 112 days declined to 48.4 .mu.g/cm/day).
D. Vincent, et al., "Maintenance of Physiologic Concentrations of Plasma Testosterone in the Castrated Male Dog, Using Testosterone-Filled Polydimethylsiloxane Capsules" Am. J. Vet. Res., 40, 705-706 (1979) discloses a reservoir device comprising a Siloxane.RTM. tube (4.65 mm.times.7.5 cm) filled with crystalline testosterone, and implanted in castrated dogs.
R. Shippy, et al., "Controlled Release of Testosterone Using Silicone Rubber" J. Biomed. Mater. Res., 7, 95-110 (1973) discloses a reservoir device comprising a crystalline testosterone cylinder dipped in Silastic.RTM. or a Silastic.RTM./testosterone suspension.
N. Cunningham, et al., "Release of Progesterone from Silicone Rubber Implants In Vitro, and the Effects of the Implants on Plasma Progesterone Levels in Sheep" J. Reprod. Fert., 43, 555-558 (1975), discloses a reservoir device comprising Silastic.RTM. tubing packed with solid progesterone, incubated in 0.9% aqueous NaCl. One implant contained progesterone dissolved in arachis oil, which resulted in a lower rate of release than the implants containing solid progesterone. The implants prepared ranged from 6 to 10 cm in length, and from 1.97 to 6.36 mm in diameter, containing from 22.5 mg to 300 mg of progesterone, but were unable to maintain an effective concentration progesterone in ewes. Cunningham also discloses solid Silastic.RTM. matrix implants containing progesterone, which achieved results superior to the reservoir devices. Matrix rods 10 cm.times.0.5 cm containing 205 to 293 mg of progesterone were capable of administering effective levels.
Additional reservoir devices are disclosed in L. Beck, et al., "Controlled-Release Delivery Systems for Hormones" Drugs, 27, 528-547 (1984): W. Greene et al., "Release Rate Of Testosterone and Estrogens from Polydimethylsiloxane Implants for Extended Periods In Vivo Compared with Loss In Vitro" Int. J. Fertil., 23, 128-132 (1978): E. Sommerville, et al., "Plasma Testosterone Level In Adult and Neonatal Female Rats Bearing Testosterone Propionate-Filled Silicone Elastomer Capsules for Varying Periods of Time" J. Endocr., 98, 365-371, (1983): U.S. Pat. Nos. 4,210,644: and 4,432,964.
U.S. Pat. No. 4,331,651 to Reul discloses a matrix device consisting of a silicone rubber depot for nasal administration to cattle. The rubber contains a "release promoting agent" which is liposoluble, scarcely soluble in water, and which may be an alcohol, ester, ether or ketone of 8-60 carbons. The "release promoting agent" should not "exude." The active compound is a steroid, optionally an antibiotic. Preferred steroids are testosterone and trenbolone acetate, optionally in combination with estrogens such as 17.beta.-estradiol, and derivatives. The active compound may be dispersed in the rubber, or may be in tablet form (optionally containing PEGs etc.) wrapped in rubber. A preferred embodiment comprises only one tablet which is partially wrapped.
Japanese application J5 9044-310A to Nippon Kayaku discloses a matrix device consisting of a silicone rubber formulation containing a crystalline powdered dissolution assistant (especially a monobasic amino acid, e.g., glycine or alanine, NaCl or mannitol) and an antibiotic or anticancer drug. These devices achieve a release time of one week to one month.
UK Patent Application 2,167,662A to Dick discloses a matrix implant device in the form of a solid cylinder. The matrix is formed from a hydrophobic polymer, and delivers 17.beta.-estradiol, testosterone, progesterone, nandrolone, trenbolone, or their acetates, propionates, benzoates, or zeranol, or combinations thereof. Dick discloses, as matrix materials, insoluble polypropylene, polyethylene, polyvinyl chloride, ethylvinyl acetate, polystyrene and polymethacrylate, as well as glycerol esters of the glycerol palmitostearate, glycerol stearate and glycerol behenate type.
D. Hsieh, et al., "Enhanced Release of Drugs From Silicone Elastomers: (IV) Subcutaneous Controlled Release of Indomethacin and In Vivo/In Vitro Correlations" Drug Devel. and Indust. Pharm., 11, 1447-1466 (1985) discloses a matrix implant device comprising powdered indomethacin in a Silastic.RTM. matrix, with varying concentrations of glycerol. Addition of glycerol caused the implant to swell, and increased the release rate. D. Hsieh, et al., "Enhanced Release of Drugs From Silicone Elastomers (I) Release Kinetics of Pineal and Steroidal Hormones" Drug Devel. and Indust. Pharm., 11, 1391-1410 (1985) discloses a Silastic.RTM. matrix device containing estradiol, 0-30% glycerol, and 0 or 10% NaCl, in an aqueous cosolvent system containing 0 or 10% PEG 400, propylene glycol, or glycerol. Hsieh found that the addition of glycerol, NaCl, and cosolvents increased the flux obtained from the matrix implant in in vitro experiments.
Matrix devices are also disclosed in P. J. Dziuk, et al., Am. J. Vet. Res., 29, 2413-2417 (1968) "Inhibition and Control of Estrus and Ovulation in Ewes with a Subcutaneous Implant of Silicone Rubber Impregnated with a Progestogen": L. Beck, et al., Drugs, 27, 528-547 (1984) "Controlled-Release Delivery Systems for Hormones": R. Heitzman, J. Animal Sci., 57, 233-238 (1983) "The Absorption, Distribution and Excretion of Anabolic Agents": J. Wagner, et al., J. Animal Sci., 58, 1062-67 (1984) "Effect of Monensin, Estradiol Controlled Release Implants and Supplement on Performance in Grazing Steers": N. Scheffrahn, et al., J. Animal Sci., 51, 108-109, "Induction of Male Sex Behavior In Ewes Using Silastic Implants Containing Testosterone Propionate": and N. Cunningham, et al., J. Reprod. Fert., 43, 555-558 (1975), "Release of Progesterone from Silicone Rubber Implants In Vitro, and the Effects of the Implants on Plasma Progesterone Levels in Sheep".
U.S. Pat. No. 3,948,254 to Zaffaroni discloses a hybrid device comprising a solid matrix drug reservoir encapsulated in a microporous membrane, where the membrane pores are filled with a carrier material. The drugs disclosed include hormonal agents such as prednisolone, cortisone, cortisol and triamcinolone; androgenic steroids, such as methyltestosterone, fluoximesterone and the like; estrogenic steroids such as 17.beta.-estradiol and ethinyl estradiol; progestational steroids, for example 17.alpha.-hydroxyprogesterone acetate, 19-norprogesterone, norethindrone, and the like.
UK Patent Application 2,154,138A to Roche discloses a hybrid subcutaneous implant for livestock weight promotion, using silicone rubber (Silastic, especially dimethylpolysiloxane) with estradiol dispersed in the rubber. The device is formed as a substantially hollow cylinder of the silicone rubber, with a core consisting of active ingredients (which may be steroids) dispersed in a biocompatible, biosoluble polymer which dissolves within days of implantation. The biocompatible, biosoluble polymer is a mixture of high molecular weight polyethylene glycol (PEG) and low molecular weight PEG, for example, PEG 3,000-10,000 with PEG 200-600. Thus, estradiol is released as if from a matrix (the silicone rubber wall), while the second active compound is released from a reservoir.
UK Application 2,136,688A to Ferguson discloses a delivery device of the type described in Roche above, but with an external dusting of antibiotic to improve retention.
U.S. Pat. No. 3,992,518 to Chien discloses another hybrid device comprising a membrane-wrapped silicone rubber matrix. The rubber matrix is prepared by forming an emulsion of rubber monomer and active compound in aqueous solution with a hydrophilic cosolvent, then crosslinking the monomer to form "microsealed compartments" containing the active compound in solution. The resulting matrix is then coated with a rate-controlling membrane. The rate-controlling membrane may be silicone rubber, ethylene/vinyl acetate, polyethylene terephthalate, butyl rubber, etc. The active compound is in a solution of water and a hydrophilic cosolvent not soluble in the rubber matrix. The hydrophilic cosolvent may be polyethylene glycol, propylene glycol, butylene glycol, etc., with PEG 400 preferred at a concentration of 20-70%. The hydrophilic cosolvent may also be an ionic or neutral surface active agent in aqueous concentration above the critical micelle concentration, preferably sodium dodecyl sulfate, polysorbates, cetyl trimethylammonium bromide, or cetylpyridinium chloride. Active compounds disclosed include ethynodiol diacetate, ethylnyl estradiol, estrone, estradiol, other estrogens, progesterone, and testosterone.
We have now found that one may prepare a particularly advantageous subcutaneous implant form by formulating compressed pellets containing a biologically active compound, a solubilizing agent, a solid, hydrophilic, non-toxic polymer sufficient to cause swelling by osmotic pressure after implantation, followed by wrapping the pellet(s) in a rate-controlling membrane which is permeable to the biologically active compound but is impermeable to the solubilizing agent. The implants so obtained are particularly advantageous in a number of respects:
a long, zero-order release of greater than 90% of encapsulated biologically active compound is effected (zero-order release for greater than 230 days is attainable with the preferred embodiments); PA1 the length of the release period is a linear function of the amount of biologically active compound encapsulated, e.g., adding 20% more biologically active compound to an implant will result in a release period extended by 20% with no change in the rate of release per day; PA1 the biologically active compound is essentially completely administered (i.e., little or no undelivered residue remains within the device); PA1 use of the solubilizing agent increases the flux of biologically active compound through the rate-controlling membrane, thus allowing one to achieve a suitable flux with less membrane surface area (which in turn allows fabrication of a smaller device); PA1 the implant is small and easily administered--due to its small dimensions, it may be implanted using a hollow needle (cf. Norplant.RTM. a five-year human contraceptive implant containing progestin, which requires six "matchstick-sized" capsules, and which results in overdosing during the first year in order to maintain sufficient levels for contraception during the following years); PA1 because the solubilizing agent is trapped inside the membrane, only a small amount is required, and the agent need not be non-irritating; PA1 the complete device is easily and inexpensively manufactured; and PA1 treatment may easily be terminated by removing the implant device.